title: The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's syndrome.
abstract: Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin has pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating the organ size, cell proliferation, and differentiation. We now show that Hippo signaling is required for SMG-branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from non-obese diabetic mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and connective tissue growth factor, known downstream targets of TAZ. Our studies show that Hippo signaling has a crucial role in SMG-branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans.
authors.affiliation: Department of Oral Surgery and Oral Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tone B
authors.initials: TB
authors.lastname: Enger
authors.forename: Arman
authors.initials: A
authors.lastname: Samad-Zadeh
authors.forename: Meghan P
authors.initials: MP
authors.lastname: Bouchie
authors.forename: Kathrine
authors.initials: K
authors.lastname: Skarstein
authors.forename: Hilde K
authors.initials: HK
authors.lastname: Galtung
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mera
authors.forename: Janice
authors.initials: J
authors.lastname: Walker
authors.forename: A Sue
authors.initials: AS
authors.lastname: Menko
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.forename: Denise L
authors.initials: DL
authors.lastname: Faustman
authors.forename: Janicke L
authors.initials: JL
authors.lastname: Jensen
authors.forename: Maria A
authors.initials: MA
authors.lastname: Kukuruzinska
mesh_terms: D000217:Acyltransferases; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D016022:Case-Control Studies; D016764:Cell Polarity; D004195:Disease Models, Animal; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009024:Morphogenesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D013363:Submandibular Gland / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051178:alpha Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases